Central venous access is an important tool for the appropriate treatment and support of patients for many life-threatening diseases such as cancer and end-stage kidney failure. However, intravascular (IV) catheters put patients at risk for catheter occlusion as well as systemic infections. Despite routine flushing with heparin or saline, 41% of central venous catheters (CVCs) result in catheter occlusion, which markedly increases the risk of infection. These infections represent a significant problem among large sections of population, are responsible for high attributable mortality (12-25%) and morbidity, and are expensive to manage (estimated cost to the healthcare system is approximately $4.6 billion per year).
Therefore, there is a need for a product that can address both catheter occlusion and infections associated with indwelling medical devices (IMDs). All CVCs when not used for their intended function such as delivery of chemo- or bio-therapeutics, parenteral nutrition, or hemodialysis must be “locked” with a Catheter Lock Solution (CLS). The locking time depends on the primary use of the catheters and it can be as short as 1 hr at Intensive Care Units (ICUs) and to up to 10 days for outpatient oncology patients.
The primary function of CLS is to provide a physical barrier to the back flow of blood into the catheter thereby maintaining catheter patency. Prior art CLS formulations contain substances such as heparin or trisodium citrate intended to prevent blood clotting within the catheter. Prior art CLS formulations also contain other substances such as taurolidine, ethanol, gentamicin or other antibiotics to inhibit microbial growth in catheter lumens.
Both Gram positive and negative bacteria including drug-resistant pathogens, as well as clinical species of fungi, commonly colonize catheter lumens and form a drug resistant microbial biofilm. Microbial biofilms can shed microbial colonies into the bloodstream leading to infections and sepsis. Therefore, prevention of biofilm formation and eradication of existing biofilm is a necessary prerequisite of successful new CLS formulations.
In the past two decades the efficacy of various innovative CLS were tested in vitro and in vivo for prevention of catheter occlusion and Central Line Associated Blood Stream Infections (CLABSI). Unfortunately most, if not all, failed the expectations. For example, a lock solution containing 4% trisodium citrate and taurolidine, while it somewhat reduced CLABSI in a clinical study, significantly increased occlusion events by causing blood coagulation inside the catheter. Similar results were reported for another citrate-containing lock solution ZURAGEN.
Another problem with citrate and taurolidine-containing lock solutions such as TAUROLOCK is the low physical stability of nearly saturated solutions and tendency to form precipitation even at small temperature changes, as noted in a TAUROLOCK CE Mark package insert. Another example of failed attempt was to use 70% ethanol as CLS in a control clinical study in oncology patients. Seventy percent (70%) ethanol has demonstrated antimicrobial activity and anticoagulation activity, nevertheless, it failed in a study due to a very low density and viscosity of 70% ethanol and the resulting difficulty to install and maintain this experimental CLS within catheter lumens.
Another problem with prior art CLS formulations, including various combinations of antibiotics and heparin or citrate, is an inability to eradicate mature biofilm. While most of them have measurable MIC (minimum inhibitory concentration) against bacteria and can prevent biofilm formation, none has proven efficacy in eradicating bacterial and fungi biofilms. After CVC insertion, the lumens are covered rapidly by a thrombin layer, rich in host-derived proteins, that forms a conditioning film and promotes surface adherence of microbial colonizers. In addition, thrombin converts soluble fibrinogen into insoluble strands of fibrin, which acts as an accelerant for biofilm formation.
A CLS that is unable to eradicate such fibrin/biofilm will fail to significantly reduce both, CLABSI and occlusion events. Finally, antibiotics frequently used in prior art CLS formulations have low solubility and reduced activity against drug resistant pathogens. Therefore, in lock solutions those antibiotics are used at concentrations very close to their saturation points which limits the physical stability of final solutions, leads to precipitation, substandard concentration and may cause bacterial resistance.